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J. Org. Chem. 1999, 64, 1430-1431
Communications One-Pot Synthesis of Amides and Esters from 2,2,2-Trihaloethyl Esters Using Phosphorus(III) Reagents Jeremy J. Hans, Russell W. Driver, and Steven D. Burke* Department of Chemistry, University of WisconsinsMadison, 1101 University Avenue, Madison, Wisconsin 53706-1369 Received December 3, 1998
The synthesis of amides and esters from carboxylic acid derivatives is a transformation of general synthetic interest. Preparation of complex amides and esters from protected carboxylic acids is generally achieved by carboxylic acid deprotection followed by formation of an activated acyl species and treatment with an amine or alcohol nucleophile. Such a deprotection/condensation protocol requires two or more steps and can be attended by difficulties in working with the free carboxylic acid intermediate. The 2,2,2-trichloroethyl group is a useful protecting group for carboxylic acids,1 and the 2,2,2-tribromoethyl group has also been used in this capacity.2 The removal of trihaloethyl esters has been accomplished with a variety of reductive methods, the most popular being treatment with zinc. The use of phosphorus(III) compounds for the reductive cleavage of trichloroethyl-protected phosphotriesters has also been reported,3 presumably involving formation of an electrophilic phosphonium species in addition to liberation of the dialkyl phosphate anion and 1,1-dichloroethylene. Although phosphonium salts have long been used to activate carboxylate functional groups in condensation reactions,4,5 in situ formation of these species by reduction of trihaloethyl esters to effect condensation reactions has not been exploited. Herein we report amidation or transesterification of trihaloethyl esters using phosphorus(III) compounds, as generalized in eq 1. This one-pot deprotection, activation, and condensation sequence provides an operationally simple method for the title transformations.
The conversion of 2,2,2-tribromoethyl benzoate (1a) to N-butylbenzamide (2) using hexamethylphosphorous tri* To whom correspondence should be addressed. Tel: (608) 262-4941. Fax: (608) 265-4534. E-mail:
[email protected]. (1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991. (b) Woodward, R. B.; Heusler, K.; Gosteli, J.; Naegeli, P.; Oppolzer, W.; Ramage, R.; Ranganathan, S.; Vorbruggen, H. J. Am. Chem. Soc. 1966, 88, 852. (2) (a) Stark, W. M.; Hawker, C. J.; Hart, G. J.; Philippides, A.; Petersen, P. M.; Lewis, J. D.; Leeper, F. J.; Battersby, A. R. J. Chem. Soc., Perkin Trans. 1 1993, 23, 2875. (b) Weiguny, J.; Schafer, H. J. Liebigs Ann. Chem. 1994, 225. (3) (a) Letsinger, R. L.; Groody, E. P.; Tanaka, T. J. Am. Chem. Soc. 1982, 104, 6805. (b) Letsinger, R. L.; Groody, E. P.; Lander, N.; Tanaka, T. Tetrahedron 1984, 40, 137.
amide (HMPT) was selected to determine the optimal reaction conditions (Table 1). The tribromoethyl ester provides a softer, more reactive halogen electrophile than its trichloroethyl ester counterpart, and HMPT was chosen for its high nucleophilicity.6 Treatment of 1a with 1.2 equiv of HMPT, 1 equiv of butylamine, and 2.5 equiv of triethylamine in THF at 0 °C provided 2 in 36% yield (entry 1). Use of benzene as a nonpolar solvent gave a similar yield (entry 2), while more polar solvents such as acetonitrile (entry 3) or dimethylformamide (DMF, entry 4) facilitated the reaction, with DMF providing the best yield. Lowering the reaction temperature improved the yield of 2 to 83% (entry 5). Small amounts of 2,2-dibromoethyl benzoate and N,Ndimethylbenzamide were isolated byproducts in these reactions. Investigation of the choice of reductant and electrophile revealed the combination of HMPT and tribromoethyl protecting group to be the most effective for amide synthesis (Table 2). The reaction of HMPT with 1a proceeded rapidly at -55 °C (entry 1). The use of tributylphosphine slowed the reaction and provided 2 in reduced yield (entry 2). Decreasing the nucleophilicity of the phosphorus reagent by using triphenylphosphine markedly slowed the reaction at room temperature (entry 3), resulting in a 24% yield of 2 after 48 h. This yield is similar to that of the corresponding control experiment conducted in the absence of phosphine (entry 4). Heating the triphenylphosphine reactions produced yields only marginally higher than controls. Use of the trichloroethyl ester necessitated the use of higher temperatures to afford complete consumption of starting material, and lower yields were obtained (entries 5 and 6). Using the optimized conditions, secondary and tertiary amides of aromatic and aliphatic acids as well as a protected alanylalanine dipeptide have been synthesized from the corresponding tribromoethyl esters (Table 3). Modification of the amide synthesis conditions allowed for the synthesis of esters using this strategy. Initial attempts to effect the transesterification of trihaloethyl esters by addition of HMPT to tribromoethyl esters failed to produce the desired products. The use of PBu3 as phosphine reagent gave the ester products, albeit in low yield (Table 4, entry 1). Addition of 2 equiv of the acylation catalyst 4-(N,Ndimethylamino)pyridine (DMAP)7 markedly improved yields in both HMPT- and tributylphosphine-induced reactions. In contrast to the amidation reactions, tributylphosphine provided yields of ester products superior to those obtained with HMPT. Substantial amounts of N,N-dimethylamide products were observed when HMPT was used as reductant, presumably resulting from attack on activated acyl intermediates by dimethylamine liberated by the alcoholysis of HMPT.8 In support of this theory, HMPT underwent methanolysis (4) (a) Hruby, V. J.; Barstow, L. E. J. Org. Chem. 1971, 36, 1305. (b) Yamada, S.; Takeuchi, Y. Tetrahedron Lett. 1971, 3595. (c) Castro, B.; Dormoy, J.-R. Bull. Soc. Chim. Fr. 1971, 3034. (d) Castro, B.; Dormoy J. R. Tetrahedron Lett. 1972, 4747. (e) Castro, B.; Dormoy, J.-R.; Evin, G.; Selve, C. Tetrahedron Lett. 1975, 1219. (f) Coste, J.; Le-Nguyen, D.; Castro, B. Tetrahedron Lett. 1990, 31, 205. (g) Coste, J.; Fre´rot, E.; Jouin P. J. Org. Chem. 1994, 59, 2437. (5) (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801. (b) Kim, M. H.; Patel, D. V. Tetrahedron Lett. 1994, 35, 5603. (c) Coste, J.; Campagne, J.-M. Tetrahedron Lett. 1995, 36, 4253. (6) Castro, B. R. Org. React. 1983, 29, 1. (7) (a) Ho¨fle, G.; Steglich, W.; Vorbrueggen, H. Angew. Chem., Int. Ed. Engl. 1978, 17, 569. (b) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129. (c) Hassner, A. In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, 1995; p 2022.
10.1021/jo9823700 CCC: $18.00 © 1999 American Chemical Society Published on Web 02/17/1999
Communications
J. Org. Chem., Vol. 64, No. 5, 1999 1431
Table 1. Initial Studies of Amide Formation
Table 4. Synthesis of Esters from Trihaloethyl Esters
entry
solvent
T (°C)
% yield of 2a
1 2 3 4 5
THF benzene CH3CN DMF DMF
0 0 0 0 -55
36 35 70 75 83
a
entry
trihaloethyl ester
alcohol (R′OH)
product
% yielda
1 2 3 4 5 6 7 8 9 10 11 12 13
1a 1a 1a 1a 1a 1a 3 3 3 3 3 1a 1b
CH3O(CH2)2OH CH3O(CH2)2OH BuOH BnOH 2-pentanol (-)-menthol CH3O(CH2)2OH BuOH BnOH 2-pentanol (-)-menthol t-BuOHc CH3O(CH2)2OH
8a 8a 8b 8c 8d 8e 9a 9b 9c 9d 9e 8f 8a
21b 69 81 77 62 61 74 65 70 63 65 11 44d
Isolated yields.
Table 2. Effect of Phosphorus Nucleophile and Halogen on the Synthesis of 2
a Isolated yields. b Reaction conducted in the absence of DMAP. 1:1 DMF/t-BuOH was used as solvent. d Reaction temperature ) 100 °C.
c
entry
X
phosphorus rgt
T (°C)
time (h)
% yield of 2a
1 2 3 4 5 6
Br Br Br Br Cl Cl
HMPT PBu3 PPh3 none HMPT PBu3
-55 -55 f 0 rt rt rt 90
0.5 1.2 48 48 4.5 3.5
83 25 24b 17c 18 39
a Isolated yields. b 42% of 1a was recovered. c 66% of 1a was recovered.
Table 3. Optimized Conversion of Tribromoethyl Esters to Amides
entry
trihaloethyl ester
amine
product
% yielda
1 2 3 4 5
1a 1a 3 3 4
HNEt2 HCl‚GlyOEt BuNH2 HNEt2 HCl‚AlaOEt
5a 5b 6a 6b 7
76 77 88 57 70
a
Isolated yields.
when subjected to similar reaction conditions in the absence of tribromoethyl ester.9 The reduced nucleophilicity of alcohols relative to amines allows attack by dimethylamine to become a competitive reaction pathway in the HMPTmediated transesterifications. Esters of both primary and secondary alcohols were produced in good yields using the tributylphosphine-DMAP procedure (Table 4, entries 2-11). Acylation of tert-butyl alcohol proved difficult, giving only 11% of the tert-butyl (8) (a) Petrov, K. A.; Nifant’ev, EÄ . E.; Lysenko, T. P.; Evdakov, V. P. Zh. Obshch. Khim. 1961, 31, 2377. (b) Nifant’ev, EÄ . E.; Ivanova, N. L.; Fursenko, I. V. Zh. Obshch. Khim. 1969, 39, 854. (c) Houalla, D.; Sanchez, M.; Wolf, R. Bull. Soc. Chim. Fr. 1965, 2368. (9) A solution of HMPT in DMF was treated with methanol (1.4 equiv), DMAP (1 equiv), and 4-(N,N-dimethylamino)pyridinium trifluoroacetate (DMAP‚TFA, 0.4 equiv). Phosphorus NMR analysis of an aliquot of this reaction mixture after 10 min showed no HMPT resonance (122.7 ppm) and two downfield resonances that correspond to MeOP(NMe2)2 (137.9 ppm) and (MeO)2PNMe2 (147.6 ppm). This spectrum is similar to the 31P spectrum obtained in the ethanolysis of HMPT (ref 8c).
benzoate ester when tert-butyl alcohol was used as cosolvent (entry 12). As a control, treatment of 1a with 2-methoxyethanol and DMAP in the absence of phosphine for 24 h at room temperature produced no product by TLC analysis. As with the amidation reactions, the use of the trichloroethyl ester derivatives required higher temperatures for starting material consumption and provided lower yields (entry 13). The mechanism implied in eq 1, involving an acyloxyphosphonium intermediate,4b-d,g,5 is supported by the observation of 1,1-dibromoethylene by proton and carbon NMR analysis of the crude distillates from reaction mixtures in the conversion of 1a to 2 and 1a to 8a. Furthermore, 1H NMR coupling constants for menthol-derived esters 8e and 9e revealed a retention of configuration at the carbinol carbon. Thus, esterification does not proceed by a Mitsunobutype inversion in which the alcohol is activated by a phosphonium species and then displaced by a carboxylate anion.10 The beneficial effect of catalytic DMAP in transesterification reflects the lower nucleophilicity of alcohols, relative to amines. In summary, secondary and tertiary amides have been synthesized in moderate to good yields from tribromoethyl esters in one step by treatment with HMPT and amine. Similarly, esters of primary and secondary alcohols have been prepared from tribromoethyl esters by treatment with tributylphosphine in the presence of DMAP. Trichloroethyl carboxylates gave lower yields of ester and amide products when subjected to these reaction conditions. This method conveniently bypasses the free acid form of the substrate and provides a direct and efficient method for the conversion of protected carboxylic acids to esters or amides.
Acknowledgment. This research was supported by NIH Grant Nos. GM 28321 and CA74394. Additional support from Merck and Pfizer is gratefully acknowledged. The University of Wisconsin NMR facility receives financial support from NSF (CHE-9208463) and NIH (1S10 RR0 8389-D1). Supporting Information Available: Experimental procedures, characterization data, and 1H and 13C NMR spectra for compounds 1-9.
JO9823700 (10) (a) Mitsunobu, O. Synthesis 1981, 1. (b) Hughes, D. Org. React. 1992, 43, 335.
